Biomedical Engineering Reference
In-Depth Information
or to the potential of electron-deficient 4-aryl moieties behaved as electron
acceptors in charge transfer mechanism [
82
].
X-ray as well as (Q)SAR analyses of several series of dihydropyridine analogs
[
68
] resulted that the torsion angle of the bond between the aryl and the 1,
4-dihydropyridine ring is fixed by lactone bridges of different chain lengths.
These findings were used in a lead optimization program from which a second
generation analog,
lacidipine,
with a sustained duration of action, potency, and
selectivity was derived [
83
] (Fig.
3
). In
lacipidine
, the ester group is the bulky
tert
-butyl moiety. It is a competitive calcium ions antagonist with high lipophilicity.
Its pharmacological profile was studied extensively both in vitro and in vivo
.
Furthermore, it was found to present antioxidant activity [
84
] equipotent to vitamin
E in many tests. Lacidipine also showed a direct protective effect on the vasculature
at non-anti-hypertensive doses, indicating that its high lipophilic character com-
bined with antioxidant ability, selectivity, potency, significant antiatheromatic
activity, and sustained duration of action might be beneficial for elderly patients
[
85
,
86
].
2.2.2 Nondihydropyridines
Phenylalkylamines
Phenylalkylamines [
87
] are thought to access calcium ion channels from the
intracellular side, although this evidence is not well defined. The drugs of this
class are relatively selective for myocardium. They reduce myocardial oxygen
demand and reverse coronary vasospasm, and they are often used to treat angina.
They present minimal vasodilatory effects compared to dihydropyridines. Thus,
their major mechanism of action is causing negative inotropy.
Representative agents belonging to this class are: verapamil (Calan, Isoptin) and
gallopamil (Procorum, D600) (Fig.
11
).
Verapamil is the most widely used phenylalkylamine. It mainly gets access to
the binding domain when the channel is open. As an organic cation, it blocks the
channel by interfering with Ca
2
รพ
ion binding to the extracellular mouth of the
pore and slows the recovery of channels from inactivation. Once bound to the open
state, it can promote the inactivated channel conformation. Verapamil has two
enantiomers with different kinetics and activity. The (
S
) isomer is more active but
has a shorter half-life and lower bioavailability than the (
R
) isomer. The higher
proportion of (
S)
isomer that is available is the major reason why
intravenous
verapamil has more cardiac effects for a given serum concentration than oral
verapamil.
The more active methoxyverapamil (gallopamil) is also licensed for clinical use
in some countries.
Verapamil analogs were subjected to a QSAR analysis from which was found
that along with the electronic property, the size of the substituents (molecular
volume of the ring substituents) will also be important for their activity [
88
].
